Heparin and its structurally related heparan sulfate, the linear sulfated polysaccharides belonging to the family of glycosamino-glycans, play significant roles in a diverse set of biological processes, including blood coagulation, virus infection cell growth, inflammation, wound healing, tumor metastasis, lipid metabolism, and diseases of the nervous system. Heparin has a well-established utility as an anticoagulant drug and contains a trisulfated disaccharide repeating unit as the major component consisting of alternating D-glucosamine and L-iduronic acid with alpha 1→4 linkages:

Enzymatic degradation of heparin with heparinase gives a mixture of oligosaccharides with even sugar units invariably having an unsaturated D-glucuronic acid residue at the non-reducing end:

Low molecular weight heparins and heparinoids such as fondaparinux sodium (ARIXTRA), methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl-(1→4)-O-beta-D-glucopyranuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl-(1→4)-O-2-O-sulfo-alpha-L-idopyranuronosyl-(1→4)-2-dexoy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranoside, decasodium salt and tinzaparin sodium (INNOHEP):
are FDA approved antithrombotics with well-known utilities for the prevention of blood clotting. Tinzaparin sodium is obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum resulting in molecular weight distributions from <2,000 daltons to >8,000 daltons. Similarly, low molecular weight heparins and heparinoids including dalteparin, enoxaparin, ardeparin, certoparin, nadroparin, pamaparin, and reviparin are obtained by depolymerization methods of mucosa resulting in compositions having various molecular weight distributions.
Low molecular weight heparins of varying molecular weights can have substantial therapeutic implications, such as undesirable side effects. It is well known that producing therapeutics with more homogeneous compositions can decrease side effects. For example, current low molecular weight heparins and heparinoids when concurrently used with spinal epidural anesthesia, or spinal puncture may cause bleeding or hematomas (collection of blood) within the spinal column. When bleeding occurs in the spinal column, increased pressure on the spinal cord may result in permanent paralysis. The exact reason for this occurrence is not understood; however, it is hypothesized to be the side effect of one or more of undesirable low molecular weight heparin or heparinoid compositions or conformations. Thus, there is a need for improved methods of obtaining low molecular weight heparins polymers that are substantially pure and have homogeneous structural configurations, confirmations, and stereomeric compositions.
The frequently encountered problems in the synthesis of polymeric heparin molecules with substantially homogeneous compositions include the generation of rare L-idose, the differentiation of the isomeric configuration of hydroxyl groups on each sugar residue, stereocontrol in the construction of alpha and beta-glycosidic bonds, the cleavage of multi-protecting groups, and the transformation of multi-functional groups. Thus, there is a need for synthetic methods of producing low molecular weight heparins and heparinoid that reduce the efforts for the generation of L-idose, allow the cleavage of multiple protecting groups, differentiation of hydroxyl groups on the sugar residues and allow for the control of the construction of alpha and beta-glycosidic bonds.